WO2020178768A1 - 3'3'-cyclic dinucleotide analogue comprising a cyclopentanyl modified nucleotide as sting modulator - Google Patents

3'3'-cyclic dinucleotide analogue comprising a cyclopentanyl modified nucleotide as sting modulator Download PDF

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WO2020178768A1
WO2020178768A1 PCT/IB2020/051883 IB2020051883W WO2020178768A1 WO 2020178768 A1 WO2020178768 A1 WO 2020178768A1 IB 2020051883 W IB2020051883 W IB 2020051883W WO 2020178768 A1 WO2020178768 A1 WO 2020178768A1
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compound
inhibitors
pharmaceutically acceptable
independently
acceptable salt
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PCT/IB2020/051883
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English (en)
French (fr)
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Gabriel Birkus
Petra BREHOVA
Milan DEJMEK
Radim NENCKA
Ondrej PAV
Michal Sala
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Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I.
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Priority to EP20712040.3A priority Critical patent/EP3935065A1/de
Priority to US17/434,336 priority patent/US11766447B2/en
Publication of WO2020178768A1 publication Critical patent/WO2020178768A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7084—Compounds having two nucleosides or nucleotides, e.g. nicotinamide-adenine dinucleotide, flavine-adenine dinucleotide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
    • C07F9/6574—Esters of oxyacids of phosphorus
    • C07F9/65746—Esters of oxyacids of phosphorus the molecule containing more than one cyclic phosphorus atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals
    • C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
    • C07H19/207—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids the phosphoric or polyphosphoric acids being esterified by a further hydroxylic compound, e.g. flavine adenine dinucleotide or nicotinamide-adenine dinucleotide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals
    • C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
    • C07H19/213—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids containing cyclic phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55561—CpG containing adjuvants; Oligonucleotide containing adjuvants

Definitions

  • the present disclosure relates to novel 3'3'-cyclic dinucleotides comprising a carbocyclic nucleotide, compositions comprising such compounds, methods for their synthesis, and their use in the therapy of various conditions.
  • the immune system has evolved mechanisms to eliminate pathogens and to maintain the homeostasis of the host. It can be principally divided into two branches: innate and adaptive immunity.
  • the innate immune system recognizes the presence of pathogen or disruption of the homeostasis of the host by a battery of Pattern Recognition Receptors (PRRs) which detect a small set of ligands associated with pathogens or damage. These ligands are generally called Pathogen Associated Molecular Patterns (PAMPs) or Damage Associated Molecular Patterns (DAMPs) (Takeuchi O et al, Cell, 2010: 140, 805-820).
  • PAMPs Pathogen Associated Molecular Patterns
  • DAMPs Damage Associated Molecular Patterns
  • PRRs have been identified over past two decades including Toll-like receptors, retinoic acids inducible gene (RIG-I)-like receptors, nucleotide-binding oligomerization domain-like (NOD) receptors, C-type lectin receptor and cytosolic DNA sensors (Brubaker SW et al, Annu Rev Immunol, 2015:33,257-290).
  • RIG-I retinoic acids inducible gene
  • NOD nucleotide-binding oligomerization domain-like receptor
  • C-type lectin receptor C-type lectin receptor
  • cytosolic DNA sensors Brubaker SW et al, Annu Rev Immunol, 2015:33,257-290.
  • Recognition of PAMPs and DAMPs by PRRs ultimately leads to the upregulation of cytokines and chemokines, including interferons, and recruitment of immune cells to the sites of infection. All of these processes slow down pathogen replication and contribute to the development of adaptive immunity
  • Cellular DNA is normally restricted to the nucleus and mitochondria of healthy cells. DNA present in cytosol, therefore, represents a signal indicating the presence of pathogen or disruption of the host homeostasis.
  • the sensing of exogenous DNA in cytosol of host cells initiates two distinct innate immune signaling cascades. The first includes AIM2 (absent in melanoma 2) and interferon-inducible protein 16 (IFI16) and induces formation of an inflammasome complex, which in turn processes pro-interleukin (IL) 1b and pro-IL-18 to active cytokines (Wang Q at al. Expert Opin. liter. Targets, 2015: 19, 113).
  • AIM2 abent in melanoma 2
  • IFI16 interferon-inducible protein 16
  • the second pathway involves DNA-dependent activator of IRFs (DAI), DEAD box polypeptide 41 (DDX41) and cyclic GMP-AMP synthase (cGAS, also referred to as MB21D1) and triggers activation of the transcription factors NFK-B (nuclear factor kappa B) and IRF-3 (interferon regulatory factor 3) via adaptor protein STING (Stimulator of Interferon Genes, also called TMEM173, MGGA, ERIS) (Schholzner L, Immunology, 2013: 218, 1312-1321).
  • DAI DNA-dependent activator of IRFs
  • DDX41 DEAD box polypeptide 41
  • cGAS cyclic GMP-AMP synthase
  • STING adaptor protein can be activated by the second messenger cyclic dinucleotides (CDNs) (Burdette et al. Nature 2011: 478,515-518).
  • CDNs with affinity to STING contain two purine nucleotide monophosphates linked with either two 3'-5' (3'3'- CDNs), two 2'-5' (2'2'-CDNs) or 2'-5' and 3'-5' phosphodiester bonds (2'3'-CDNs).
  • the prototype 2'3'-cGAMP (c[G(2',5')pA(3',5')p]) is a product of the activation of host cGAS protein in the presence of pathogen or self dsDNA (Zhang et al, Molecular Cell 2013:51,226-
  • STING Activation of STING ultimately results in release of type I and III interferons and variety of cytokines and chemokines such as IL-6, TNF-a and INF-g.
  • the type I interferons are immune-regulatory cytokines that play a pivotal role in viral immunity. They can induce dendritic cell (DC) and macrophage maturation and activation (Galluci et al, Nat Med, 1999:5, 1249-1255) and can promote T- and B-cell survival, activation and differentiation. Furthermore, the interferons are capable of activating numerous intracellular pathways that inhibit virus replication. The clinical utility of type I interferons has been demonstrated by their usefulness in treatment of chronic hepatitis B and C (Lin and Young, Cytokine Growth Factor Rev, 2014:25,369-376).
  • interferons have shown utility in treatment of human cancers (Cohen et al, N Engl J Med, 2005:353,2477-2490, Tsao et al, N Engl J Med, 2004:351,998-1012).
  • Type I IFNs can act on immune cells to induce antitumor response (Musella et al, Oncoimmunology 2017:6:el314424).
  • Type I IFN signaling was shown to be important in tumor-initiated T cell priming in mice. Animals lacking the IFN- a/b receptor in dendritic cells were unable to reject immunogenic tumors, and were defective in antigen cross-presentation to CD8+ T cells (Fuertes et al, J Exp Med, 2011:208, 2005- 2016, Diamond et al, J Exp Med, 2011:208: 1989-2003). Consistent with these
  • CDNs are believed to promote priming of both cellular and humoral immunity.
  • CDNs were shown to be an effective adjuvant in animal models (Dubensky et al, Ther Adv Vaccines, 2013:1,131-143.
  • WO 2018/013908, WO 2018/013887, WO2018/009652, WO 2018/009648, and WO 2018/009466 disclose certain compounds and their use in inducing an immune response.
  • Administration of a small molecule agonist of STING could result in stimulation of the innate immune system response, including induction of interferons and other cytokines.
  • Such an agonist could find utility as an anti-viral and anti-cancer agent, act as an adjuvant in vaccines, or could be used in the treatment of allergic or other inflammatory diseases such as rhinitis or asthma. It is an object of this disclosure to describe novel cyclic dinucleotides and derivatives thereof that may find utility in the treatments of these diseases.
  • X 1 and X 3 are each independently OH, OR 3 , SH, or SR 3 ;
  • X 2 and X 4 are each independently O or S;
  • Y is O or CH 2 ;
  • R 1a , R 1b , R 2a , and R 2b are each independently H, OR 5 , NH 2 , or halogen; each R 5 is independently H or C 1 -C 6 alkyl;
  • each R 3 is independently C 1 -C 6 alkyl or -L-R 4 ;
  • L 1 is C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, or C 7 -C 13 alkylarylene;
  • L 2 is C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, C 6 -C 10 arylene, or
  • L 3 is C 1 -C 6 alkylene, C 2 -C 6 alkenylene, or C 2 -C 6 alkynylene;
  • R 6 is H or C 1 -C 6 alkyl
  • n 0, 1, or 2;
  • Base 1 and Base 2 are each independently
  • A, A 1 , A 2 , A 3 and A 4 are each independently H, OH, SH, F, Cl, Br, I, NH 2 , OR 15 , SR 15 , NHR 15 , N(R 15 ) 2 , or R 16 ;
  • each Z is independently O, S, or NR 15 ;
  • each Z 1 is independently O or S;
  • each R 16 is independently H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, C 2 - C 10 heterocycloalkyl, C 6 -C 10 aryl, or C 2 -C 10 heteroaryl.
  • the present disclosure includes a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of Formula (I), or a tautomer, enantiomer, hydrate, solvate, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, and/or diluent.
  • Also described herein is a method oftrealing a disease or disorder, e.g., a method of treating or preventing an infectious disease, cancer, or inflammatory disease, comprising administering to a human or animal in need thereof an effective amount of a compound of Formula (I), or a tautomer, enantiomer, hydrate, solvate, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any of the foregoing.
  • a method oftrealing a disease or disorder e.g., a method of treating or preventing an infectious disease, cancer, or inflammatory disease, comprising administering to a human or animal in need thereof an effective amount of a compound of Formula (I), or a tautomer, enantiomer, hydrate, solvate, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any of the foregoing.
  • a method of modulating the activity of STING adaptor protein to induce production of a type I interferon, cytokine and/or chemokine dependent on the STING adaptor protein e.g., inducing a STING adaptor protein-dependent type I interferon, cytokine or chemokine in a human or animal, comprising administering an effective amount of a compound of Formula (I), or a tautomer, enantiomer, hydrate, solvate, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any of the foregoing.
  • the disclosure provides novel carbocyclic nucleotides that bind to and modulate the activity of, e.g., activate, the STING adaptor protein.
  • Alkyl is a linear or branched saturated monovalent hydrocarbon.
  • an alkyl group can have 1 to 10 carbon atoms (i.e., C 1-10 alkyl) or 1 to 8 carbon atoms (i.e., C 1-8 alkyl) or 1 to 6 carbon atoms (i.e., C 1-6 alkyl) or 1 to 4 carbon atoms (i.e., C 1-4 alkyl).
  • alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl
  • Alkoxy refers to the group -O-alkyl, where alkyl is as defined above.
  • C 1-4 alkoxy refers to an -O-alkyl group having 1 to 4 carbons.
  • Alkenyl is a linear or branched monovalent hydrocarbon radical with at least one carbon-carbon double bond.
  • an alkenyl group can have 2 to 8 carbon atoms (i.e., C 2-8 alkenyl) or 2 to 6 carbon atoms (i.e., -6 alkenyl) or 2 to 4 carbon atoms (i.e., 4 alkenyl).
  • Alkenylene refers to a bivalent linear or branched monovalent hydrocarbon radical with at least one carbon-carbon double bond derived from an alkene by removal of two hydrogen atoms from different carbon atoms.
  • Alkynyl is a linear or branched monovalent hydrocarbon radical with at least one carbon-carbon triple bond.
  • an alkynyl group can have 2 to 8 carbon atoms (i.e., - 8 alkynyl) or 2 to 6 carbon atoms (i.e., -6 alkynyl) or 2 to 4 carbon atoms (i.e., C 2-4 alkynyl).
  • alkynyl groups include, but are not limited to, acetylenyl (-CoCH), propargyl (-CH 2 CoCH), and -CH 2 -CoC-CH 3 .
  • Alkynylene refers to a bivalent linear or branched monovalent hydrocarbon radical with at least one carbon-carbon triple bond derived from an alkyne by removal of two hydrogen atoms from different carbon atoms.
  • Halo or“halogen” as used herein refers to fluoro (-F), chloro (-Cl), bromo (-Br) and iodo (-I).
  • Aryl refers to a single all carbon aromatic ring or a multiple condensed all carbon ring system wherein at least one of the rings is aromatic.
  • an aryl group has 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms.
  • Aryl includes a phenyl radical.
  • Aryl also includes multiple condensed ring systems (e.g., ring systems comprising 2, 3 or 4 rings) having about 9 to 20 carbon atoms in which at least one ring is aromatic and wherein the other rings may be aromatic or not aromatic (i.e., carbocycle).
  • Such multiple condensed ring systems are optionally substituted with one or more (e.g., 1, 2 or 3) oxo groups on any carbocycle portion of the multiple condensed ring system.
  • the rings of the multiple condensed ring system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements. It is also to be understood that when reference is made to a certain atom-range membered aryl (e.g., 6-10 membered aryl), the atom range is for the total ring atoms of the aryl.
  • a 6-membered aryl would include phenyl and a 10-membered aryl would include naphthyl and 1 ,2,3,4-tetrahydronaphthyl.
  • aryl groups include, but are not limited to, phenyl, indenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, anthracenyl, and the like.
  • Arylene refers to a bivalent radical on a single aromatic ring or multiple condensed all carbon ring system, wherein at least one of the rings is aromatic, formed by removal of two hydrogen atoms from different carbon atoms on the ring or ring system.
  • an“alkylaryl” as used herein refers to an alkyl as defined herein, wherein one or more hydrogen atoms of the alkyl are independently replaced by an aryl substituent, which may be the same or different.
  • the alkyl group and the aryl group can be any of those described above.
  • an alkylaryl group has 7 to 24 carbon atoms, 7 to 16 carbon atoms, 7 to 13 carbon atoms, or 7 to 11 carbon atoms.
  • An alkylaryl group defined by the number of carbon atoms refers to the total number of carbon atoms present in the constitutive alkyl and aryl groups combined.
  • C 7 alkylaryl refers to benzyl
  • C 11 alkylaryl includes 1 -methylnaphthyl and n-pentylphenyl.
  • alkylaryl groups include, but are not limited to, benzyl, 2,2-dimethylphenyl, n-pentylphenyl, 1- methylnaphthyl, 2-ethylnaphthyl, and tire like.
  • Alkylaryl groups can be unsubstituted or substituted.
  • Alkylarylene refers to a bivalent radical on the group formed from an alkane attached to an aromatic ring, wherein the radical is formed by removal of two hydrogen atoms from each of the alkane and the aromatic ring.
  • Heteroaryl refers to a single aromatic ring that has at least one atom other than carbon in the ring, wherein the atom is selected from the group consisting of oxygen, nitrogen and sulfur;“heteroaryl” also includes multiple condensed ring systems that have at least one such aromatic ring, which multiple condensed ring systems are further described below. Thus,“heteroaryl” includes single aromatic rings of from about 1 to 6 carbon atoms and about 1-4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur. The sulfur and nitrogen atoms may also be present in an oxidized form provided the ring is aromatic.
  • heteroaryl ring systems include but are not limited to pyridyl, pyrimidinyl, oxazolyl or furyl.
  • “Heteroaryl” also includes multiple condensed ring systems (e.g., ring systems comprising 2 rings) wherein a heteroaryl group, as defined above, is condensed with one or more rings selected from heteroaryls (to form for example 1,8-naphthyridinyl), heterocycles, (to form for example 1,2,3,4-tetrahydro-1,8- naphthyridinyl), carbocycles (to form for example 5,6,7,8-tetrahydroquinolyl) and aryls (to form for example indazolyl) to form the multiple condensed ring system.
  • heteroaryls to form for example 1,8-naphthyridinyl
  • heterocycles to form for example 1,2,3,4-tetrahydro-1,8- naphthyridinyl
  • a heteroaryl (a single aromatic ring or multiple condensed ring system) has about 1-9 carbon atoms and about 1-6 heteroatoms within the heteroaryl ring.
  • Such multiple condensed ring systems may be optionally substituted with one or more (e.g., 1, 2, 3 or 4) oxo groups on the carbocycle or heterocycle portions of the condensed ring.
  • the rings of the multiple condensed ring system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements. It is to be understood that the individual rings of the multiple condensed ring system may be connected in any order relative to one another.
  • the point of attachment for a heteroaryl or heteroaryl multiple condensed ring system can be at any suitable atom of the heteroaryl or heteroaryl multiple condensed ring system including a carbon atom and a heteroatom (e.g., a nitrogen).
  • a heteroatom e.g., a nitrogen
  • the atom range is for the total ring atoms of the heteroaryl and includes carbon atoms and heteroatoms.
  • a 5 -membered heteroaryl would include a thiazolyl and a 10-membered heteroaryl would include a quinolinyl.
  • a heteroaryl ring may also be described by the number of carbons within the ring, e.g., a 5 to 10 membered heteroaryl can also be described as a C 2 -C 8 heteroaryl.
  • Exemplary heteroaryls include but are not limited to pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalyl, quinazolyl, 5, 6,7,8- tetrahydroisoquinolinyl benzofuranyl, benzimidazolyl, thianaphthenyl,
  • Heteroarylene refers to a bivalent radical on a heteroaromatic ring or ring system, wherein the radical is formed by removal of two hydrogen atoms from different carbons.
  • Cycloalkyl refers to a single saturated or partially unsaturated all carbon ring having 3 to 20 annular carbon atoms (i.e., C 3-20 cycloalkyl), for example from 3 to 12 annular atoms, for example from 3 to 10 annular atoms, or 3 to 8 annular atoms, or 3 to 6 annular atoms, or 3 to 5 annular atoms, or 3 to 4 annular atoms.
  • cycloalkyl also includes multiple condensed, saturated and partially unsaturated all carbon ring systems (e.g., ring systems comprising 2, 3 or 4 carbocyclic rings). Accordingly, cycloalkyl includes multicyclic carbocyles such as a bicyclic carbocycles (e.g., bicyclic carbocycles having about 6 to 12 annular carbon atoms such as bicyclo[3.1.0]hexane and bicyclo[2.1.1]hexane), and polycyclic carbocycles (e.g tricyclic and tetracyclic carbocycles with up to about 20 annular carbon atoms).
  • bicyclic carbocycles e.g., bicyclic carbocycles having about 6 to 12 annular carbon atoms such as bicyclo[3.1.0]hexane and bicyclo[2.1.1]hexane
  • polycyclic carbocycles e.g tricyclic and tetracyclic carbocycles with up to about 20 annular carbon
  • the rings of a multiple condensed ring system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements.
  • monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, 1- cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1- cyclohex-2-enyl and 1-cyclohex-3-enyl.
  • Heterocyclyl or“heterocycle” or“heterocycloalkyl” as used herein refers to a single saturated or partially unsaturated non-aromatic ring or a non-aromatic multiple ring system that has at least one heteroatom in the ring (i.e., at least one annular heteroatom selected from oxygen, nitrogen, and sulfur).
  • a heterocyclyl group has from 3 to about 20 annular atoms, for example from 3 to 12 annular atoms, for example from 3 to 10 annular atoms, or 3 to 8 annular atoms, or 3 to 6 annular atoms, or 3 to 5 annular atoms, or 4 to 6 annular atoms, or 4 to 5 annular atoms.
  • the term includes single saturated or partially unsaturated rings (e.g., 3, 4, 5, 6 or 7-membered rings) having from about 1 to 6 annular carbon atoms and from about 1 to 3 annular heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur in the ring.
  • the rings of the multiple condensed ring e.g.
  • bicyclic heterocyclyl system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements.
  • Heterocycles include, but are not limited to, azetidine, aziridine, imidazolidine, morpholine, oxirane (epoxide), oxetane, thietane, piperazine, piperidine, pyrazolidine, piperidine, pyrrolidine, pyrrolidinone, tetrahydrofuran, tetrahydrothiophene, dihydropyridine, tetrahydropyridine, quinuclidine, 2- oxa-6-azaspiro[3.3]heptan-6-yl, 6-oxa-1-azaspiro[3.3]heptan-1-yl, 2-thia-6- azaspiro[3.3]heptan-6-yl, 2,6-diazaspiro[3.3]heptan-2-yl, 2-azabic
  • “Substituted” as used herein refers to wherein one or more hydrogen atoms of the group are independently replaced by one or more substituents (e.g., 1, 2, 3, or 4 or more) as indicated.
  • A“compound of the present disclosure” includes compounds disclosed herein, for example a compound of the present disclosure includes compounds of Formula (I), (II), (III), and (IV), including the compounds of the Examples.
  • Treatment refers to an approach for obtaining beneficial or desired results.
  • beneficial or desired results include, but are not limited to, alleviation of a symptom and/or diminishment of the extent of a symptom and/or preventing a worsening of a symptom associated with a disease or condition.
  • “treatment” or“treating” includes one or more of the following: a) inhibiting the disease or condition (e.g.
  • Delaying refers to development of a disease or condition means to defer, hinder, slow, retard, stabilize and/or postpone development of the disease or condition. This delay can be of varying lengths of time, depending on the history of the disease and/or individual being treated. As is evident to one skilled in the art, a sufficient or significant delay can, in effect, encompass prevention, in that the individual does not develop the disease or condition.
  • Prevent or“prevention” or“preventing” as used herein refers to a regimen that protects against the onset of the disease or disorder such that the clinical symptoms of the disease do not develop.
  • “prevention” relates to administration of a therapy (e.g., administration of a therapeutic substance) to a subject before signs of the disease are detectable in the subject (e.g., administration of a therapeutic substance to a subject in the absence of detectable infectious agent (e.g., virus) in the subject).
  • the subject may be an individual at risk of developing the disease or disorder, such as an individual who has one or more risk factors known to be associated with development or onset of the disease or disorder.
  • the term“preventing HBV infection” refers to administering to a subject who does not have a detectable HBV infection an anti-HBV therapeutic substance. It is understood that the subject for anti-HBV preventative therapy may be an individual at risk of contracting the HBV virus. It is also understood that prevention does not require a 100% success rate. In some instances, prevention may be understood as a reduction of the risk of infection, but not a complete elimination the occurrence of an infection.
  • Modulation or“modulating” the activity of a protein refers to alteration of the activity such that the activity increases or decreases. In some embodiments, the modulation increases the activity.
  • “Viral infection” describes a diseased state in which a virus invades healthy cells, uses the cell's reproductive machinery to multiply or replicate and ultimately lyse the cell resulting in cell death, release of viral particles and the infection of other cells by the newly produced progeny viruses. Latent infection by certain viruses is also a possible result of viral infection.
  • “Enhancing” refers to any form of increase in the immunogenic activity of an effective dosage of a vaccine as a result of administering to an animal or a human a therapeutically effective dose of a compound of the disclosure, e.g., a compound of Formula (I), wherein said compound is administered at any time prior to, simultaneous with, or just after administration to the same animal or human of the effective dosage of a vaccine.
  • Animal refers to a mammal, for example, a domestic animal such as a pig, a cow, a horse, a dog, a cat, a rat, or a mouse, or a non-human primate such as a cynomolgus monkey or chimpanzee.
  • At risk individual refers to an individual who is at risk of developing a condition to be treated.
  • An individual“at risk” may or may not have detectable disease or condition, and may or may not have displayed detectable disease prior to the treatment of methods described herein.“At risk” denotes that an individual has one or more so-called risk factors, which are measurable parameters that correlate with development of a disease or condition and are known in the art. An individual having one or more of these risk factors has a higher probability of developing the disease or condition than an individual without these risk factors).
  • “Therapeutically effective amount” or“effective amount” as used herein refers to an amount that is effective to elicit the desired biological or medical response, including the amount of a compound that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease .
  • the effective amount will vary depending on the compound, the disease, and its severity and the age, weight, etc., of the subject to be treated.
  • the effective amount can include a range of amounts.
  • an effective amount may be in one or more doses, i.e., a single dose or multiple doses may be required to achieve the desired treatment endpoint.
  • An effective amount may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable or beneficial result may be or is achieved.
  • Suitable doses of any co- administered compounds may optionally be lowered due to the combined action (e.g., additive or synergistic effects) of the compounds.
  • “Pharmaceutically acceptable excipient” includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.
  • Co-administration refers to administration of unit dosages of the compounds disclosed herein before or after administration of unit dosages of one or more additional therapeutic agents, for example, administration of the compound disclosed herein within seconds, minutes, or hours of the administration of one or more additional therapeutic agents.
  • a unit dose of a compound of the present disclosure is administered first, followed within seconds or minutes by administration of a unit dose of one or more additional therapeutic agents.
  • a unit dose of one or more additional therapeutic agents is administered first, followed by administration of a unit dose of a compound of the present disclosure within seconds or minutes.
  • a unit dose of a compound of the present disclosure is administered first, followed, after a period of horns (e.g., 1-12 hours), by administration of a unit dose of one or more additional therapeutic agents.
  • a unit dose of one or more additional therapeutic agents is administered first, followed, after a period of hours (e.g., 1-12 hours), by administration of a unit dose of a compound of the present disclosure.
  • Co-administration of a compound disclosed herein with one or more additional therapeutic agents generally refers to simultaneous or sequential administration of a compound disclosed herein and one or more additional therapeutic agents, such that therapeutically effective amounts of each agent are present in the body of the patient.
  • “Pharmaceutically acceptable” or“physiologically acceptable” refer to compounds, salts, compositions, dosage forms and other materials which are useful in preparing a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use .
  • the compounds described herein may be prepared and/or formulated as pharmaceutically acceptable salts or when appropriate as a free base.
  • Pharmaceutically acceptable salts are non-toxic salts of a free base form of a compound that possesses the desired pharmacological activity of the free base. These salts may be derived from inorganic or organic acids or bases. For example, a compound that contains a basic nitrogen may be prepared as a pharmaceutically acceptable salt by contacting the compound with an inorganic or organic acid.
  • Non-limiting examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen-phosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates,
  • Examples of“pharmaceutically acceptable salts” of the compounds disclosed herein also include salts derived from an appropriate base, such as an alkali metal (for example, sodium, potassium), an alkaline earth metal (for example, magnesium), ammonium and N(CI-C4 alkyl)4 + . Also included are base addition salts, such as sodium or potassium salts.
  • an appropriate base such as an alkali metal (for example, sodium, potassium), an alkaline earth metal (for example, magnesium), ammonium and N(CI-C4 alkyl)4 + .
  • base addition salts such as sodium or potassium salts.
  • n is the number of hydrogen atoms in the molecule.
  • the deuterium atom is a non-radioactive isotope of the hydrogen atom.
  • Such compounds may increase resistance to metabolism, and thus may be useful for increasing the half-life of the compounds described herein or pharmaceutically acceptable salts, isomer, or a mixture thereof when administered to a mammal. See, e.g., Foster,‘Deuterium Isotope Effects in Studies of Drag Metabolism”, Trends Pharmacol. Sci., 5(12):524-527 (1984).
  • Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogen atoms have been replaced by deuterium.
  • Examples of isotopes that can be incorporated into the disclosed compounds also include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 C1, 123 I, and 125 I, respectively.
  • Substitution with positron emitting isotopes, such as 11 C, 18 F, 15 O and 13 N can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
  • PET Positron Emission Topography
  • Isotopically-labeled compounds of Formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the Examples as set out below using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.
  • the compounds of the embodiments disclosed herein, or their pharmaceutically acceptable salts may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids.
  • the present disclosure is meant to include all such possible isomers, as well as their racemic and optically pure forms.
  • Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization.
  • “scalemic mixture” is a mixture of stereoisomers at a ratio other than 1:1.
  • Stepoisomer refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable.
  • the present disclosure contemplates various stereoisomers and mixtures thereof and includes“enantiomers”, which refers to two stereoisomers whose molecules are non-superimposable mirror images of one another.
  • “Tautomer” as used herein refers to a proton shift from one atom of a molecule to another atom of the same molecule. The present disclosure includes tautomers of any said compounds.
  • “Solvate” as used herein refers to the result of the interaction of a solvent and a compound. Solvates of salts of the compounds described herein are also provided. Hydrates of the compounds described herein are also provided.
  • Prodrug as used herein refers to a derivative of a drug that upon administration to the human body is converted to the parent drug according to some chemical or enzymatic pathway.
  • COMPOUNDS [0059] Provided herein is a compound of Formula (J):
  • X 1 and X 3 are each independently OH, OR 3 , SH, or SR 3 ;
  • X 2 and X 4 are each independently O or S;
  • Y is O or CH 2 ;
  • R 1a , R 1b , R 2a , and R 2b are each independently H, OR 5 , NH 2 , or halogen; each R 5 is independently H or C 1 -C 6 alkyl;
  • each R 3 is independently C 1 -C 6 alkyl or -L-R 4 ;
  • L 1 is C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, or C 7 -C 13 alkylarylene;
  • L 2 is C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, C 6 -C 10 arylene, or
  • L 3 is C 1 -C 6 alkylene, C 2 -C 6 alkenylene, or C 2 -C 6 alkynylene;
  • R 6 is H or C 1 -C 6 alkyl
  • n 0, 1, or 2;
  • Base 1 and Base 2 are each independently
  • A, A 1 , A 2 , A 3 and A 4 are each independently H, OH, SH, F, Cl, Br, I, NH 2 , OR 15 , SR 15 , NHR 15 , N(R 15 ) 2 , or R 16 ;
  • each Z 1 is independently O or S;
  • each R 16 is independently H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, C 2 - C 10 heterocycloalkyl, C 6 -C 10 aryl, or C 2 -C 10 heteroaryl.
  • X 1 and X 3 are each independently OH, OR 3 , SH, or SR 3 ;
  • X 2 and X 4 are each independently O or S;
  • Y is O or CH 2 ;
  • R 1a , R 1b , R 2a , and R 2b are each independently H, OR 5 , NH 2 , or halogen;
  • each R 5 is independently H or C 1 -C 6 alkyl
  • each R 3 is independently C 1 -C 6 alkyl or -L-R 4 ;
  • each R 4a is independently C 1 -C 20 alkyl, C 2 - 20 alkenyl, C 2 - 20 alkynyl, -(C 1 -C 6 alkylene)-
  • L 1 is C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, or C 7 -C 13 alkylarylene;
  • L 3 is C 1 -C 6 alkylene, C 2 -C 6 alkenylene, or C 2 -C 6 alkynylene;
  • Base 1 and Base 2 are each independently
  • each R 16 is independently H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, C 2 - C 10 heterocycloalkyl, C 6 - C 10 aryl, or C 2 -C 10 heteroaryl.
  • the compound of Formula (I) has the structure of Formula
  • the compound of Formula (I) and/or (II) has the structure of Formula (III):
  • Base 1 and Base 2 are each independently:
  • A, A 1 , A 2 , A 3 and A 4 are each independently H, OH, SH, F, Cl, Br, I, NH 2 , OR 15 , SR 15 , NHR 15 , or N(R 15 ) 2 .
  • Base 1 and Base 2 are each independently:
  • Base 1 and Base 2 are each independently:
  • Base 1 and Base 2 are each independently:
  • Base 1 and Base 2 are each independently:
  • Base 1 and Base 2 are each independently:
  • Base 1 is
  • Base 1 is
  • Base 1 is
  • Base 1 is
  • Base 1 and Base 2 are each
  • a 1 is OH. In some embodiments, A 1 is NH 2 .
  • a 2 is H and A 1 is NH 2 . In some embodiments, A 2 is NH 2 and A 1 is OH.
  • a 1 , A 2 , A 3 and A 4 are each independently H, OH, or NH 2 .
  • a 1 is OH or NH 2 .
  • a 2 is H or NH 2 .
  • a 3 is H or NH 2 .
  • a 4 is NH 2 .
  • the compound of Formula (I), (II), and/or (III) has the structure of Formula (IV):
  • a 2 , and A 3 are each independently H, OH, or NH 2 .
  • a 1 is OH or NH 2 .
  • a 2 is H or NH 2 .
  • a 3 is H or NH 2 .
  • a 1 is OH or NH 2 ;
  • a 2 is H or NH 2 ; and
  • a 3 is H.
  • X 1 and X 3 are each independently OH or SH.
  • X 1 and X 3 are each OH.
  • X 1 and X 3 are each SH.
  • X 1 is SH; and X 3 is OH. In some embodiments, X 1 is OH; and X 3 is SH. [0072] In some embodiments of the compound of Formula (I), (II), (III), and/or (IV), X 1 is
  • X 1 is OR 3 ; and X 3 is OH. In some embodiments, X 1 and X 3 are each independently OR 3 . In some embodiments, X 1 is SR 3 ; and X 3 is OH. In some embodiments, X 1 is OH; and X 3 is SR 3 . In some embodiments, X 1 is SR 3 ; and X 3 is SH. In some embodiments, X 1 is SH; and X 3 is SR 3 . In some embodiments, X 1 and X 3 are each independently SR 3 .
  • each R 3 is independently -L-R 4 .
  • L 1 is C 1 -C 6 alkylene or C 7 -C 13 alkylarylene. In some embodiments, L 1 is C 1 -C 6 alkylene, such as - CH 2 -. In some embodiments, L 1 is C 7 -C 13 alkylarylene, such as -CH 2 -Ph-. [0076] In some embodiments of the compound of Formula (I), (II), (III), and/or (IV), L 2 is C 1 -C 6 alkylene, C 6 -C 10 arylene, or 5- to 10-membered heteroarylene.
  • L 2 is C 1 -C 6 alkylene or C 6 -C 10 arylene. In some embodiments, L 2 is C 1 -C 6 alkylene, such as - CH 2 -. In some embodiments, L 2 is C 6 -C 10 arylene, such as phenylene.
  • L 1 is C 1 -C 6 alkylene or C 7 -C 13 alkylarylene;
  • L 2 is C 1 -C 6 alkylene or C 6 -C 10 arylene.
  • R 4a is C 1 -C 20 alkyl, C 2 -C 20 alkenyl, C 2 - 20 alkynyl, or -(C 1 -C 6 alkylene)-(C 3 -C 14 cycloalkyl).
  • R 4a is C 3 -C 20 cycloalkyl, e.g., C 3 -C 16 cycloalkyl, C 3 -C 10 cycloalkyl, C 3 - C 8 cycloalkyl, C 3 -C 7 cycloalkyl, C 5 - C 8 cycloalkyl, or C 4 -C 7 cycloalkyl.
  • R 4a is C 1 -C 20 alkyl or -(C 1 -C 6 alkylene)-(C 3 -C 14 cycloalkyl).
  • R 4a is C 1 -C 20 alkyl or-CH 2 -(C 3 -C 14 cycloalkyl).
  • R 4a is -CH 2 -(C 3 -C 14 cycloalkyl), e.g., -CH 2 -(C 3 - C 10 cycloalkyl), -CH 2 -(C 3 - C 8 cycloalkyl), -CH 2 -
  • R 4a is C 1 -C 20 alkyl, such as C 1 -C 16 alkyl, C 3 -C 20 alkyl, C 3 -C 18 alkyl, C 3 -C 16 alkyl, C 3 -C 14 alkyl, C 3 -C 12 alkyl, C 3 - C 10 alkyl, C 3 -C 8 alkyl, C 2 -C 8 alkyl, C 1 -C 8 alkyl, C 1 -C 6 alkyl, C 2 -C 6 alkyl, or C 3 -C 6 alkyl.
  • R 4a is C 3 -C 20 alkyl.
  • X 1 is
  • R 4a is C 3 -C 20 alkyl.
  • X 1 is
  • X 1 is
  • X 1 is
  • X 1 is
  • X 1 is
  • X 3 is
  • R 4a is C 3 -C 20 alkyl.
  • X 3 is
  • R 4a is C 3 -C 20 alkyl.
  • X 3 is
  • X 3 is
  • X 3 is
  • X 3 is
  • X 3 is [0082]
  • R 2a is substitituted with 1 or 2 R 2b .
  • R 2a is substituted with one R 2b .
  • R 2b is -OH, halogen, -CN, C 1 -C 6 alkoxy, or C 1 -C 6 alkylthio. In some embodiments, R 2b is a halogen, e.g., F or Cl.
  • X 1 is OR 3 or SR 3 ;
  • R 3 is -L-R 4 ;
  • L is L 1 ;
  • L 1 is C 1 -C 6 alkylene;
  • R 4a is C 1 -C 20 alkyl.
  • X 1 is OR 3 or SR 3 ;
  • R 3 is -L-R 4 ;
  • L is L 1 ;
  • L 1 is C 7 -C 13 alkylarylene;
  • X 3 is OR 3 or SR 3 ;
  • R 3 is -L-R 4 ;
  • L is L 1 ;
  • L 1 is C 7 -C 13 alkylarylene;
  • R 5 is H or Me. In some embodiments, R 5 is H.
  • R 1a and R 1b are different. In some embodiments, at least one of R 1a and R 1b is H. In some embodiments, R 1a is H, OH, OMe, or F, and R 1b is H. In some embodiments, R 1a is H, OH or F, and R 1b is H. In some embodiments, R 1a is OH or F, and R 1b is H. In some embodiments, R 1a is OH, and R 1b is H. In some embodiments, R 1a is OMe, and R 1b is H. In some embodiments, R 1a is F, and R 1b is H.
  • R 1a is H, and R 1b is H, OH, OMe, or F. In some embodiments, R 1a is H, and R 1b is H, OH or F. In some embodiments, R 1a is H, and R 1b is OH or F. In some embodiments, R 1a is H, and R 1b is OH. In some embodiments, R 1a is H, and R 1b is OMe. In some embodiments, R 1a is H, and R 1b is F. In some embodiments, R 1a is F, and R 1b is H. In some embodiments, R 1a and R 1b are each H.
  • R 2a and R 2b are different. In some embodiments, at least one of R 2a and R 2b is H. In some embodiments, R 2a is H, OH, NH 2 , or F, and R 2b is H. In some embodiments, R 2a is H, OH or F, and R 2b is H. In some embodiments, R 2a is OH or F, and R 2b is H. In some embodiments, R 2a is OH, and R 2b is H. In some embodiments, R 2a is NH 2 , and R 2b is H. In some embodiments, R 2a is F, and R 2b is H. In some embodiments, R 2a and R 2b are each H.
  • R 1a , R 1b , R 2a , and R 2b are each independently H, OH, OMe, or F.
  • R 1a , R 1b , R 2a , and R 2b are each independently H, OH, or F.
  • at least one of R 1a and R 1b is H, and at least one of R 2a and R 2b is H.
  • R 2a is OH
  • R 2b is H
  • R 1a is F
  • R 1b is H.
  • R 2a is OH, R 2b is H, R 1a is OH, and R 1b is H.
  • R 2a is OH, R 2b is H, R 1a is H, and R 1b is OH.
  • R 2a is OH, R 2b is H, R 1a is H, and R 1b is F.
  • R 2a is OH, R 2b is H, R 1a is OMe, and R 1b is H.
  • R 2a and R 2b are each H, R 1a is OH, and R 1b is H.
  • R 1a and R 2a are each F, and R 1b and R 2b are each H. [0092] In some embodiments of the compound of Formula (I), (II), (III), and/or (IV), R 1b and R 2b are each H.
  • the compound is a compound of Formula (I), (II), (III), and/or (IV), or a pharmaceutically acceptable salt thereof.
  • a compound of Formula (I), (II), (III), and/or (IV) has the structure:
  • a compound of Formula (I), (II), (III), and/or (IV) has the structure:
  • a compound of Formula (I), (II), (III), and/or (IV) has the structure as depicted or is a tautomer, enantiomer, or pharmaceutically acceptable salt thereof.
  • a compound of the disclosure e.g, a compound of Formula (I), (II), (III), and/or (IV), can be shown in a number of equivalent depictions.
  • a compound of Formula (II) is typically depicted herein as shown above with the 3 '-substitution of each nucleoside facing each other:
  • the present disclosure provides a pharmaceutical composition
  • a compound of the present disclosure e.g. a compound of Formula (I), (II), (III), and/or (IV)
  • a pharmaceutically acceptable salt thereof e.g. a compound of Formula (I), (II), (III), and/or (IV)
  • a pharmaceutically acceptable salt thereof e.g. a compound of Formula (I), (II), (III), and/or (IV)
  • the pharmaceutical composition comprises one or more additional therapeutic agent, as more fully set forth below.
  • compositions comprising the compounds disclosed herein, or pharmaceutically acceptable salts thereof, may be prepared with one or more
  • compositions may be prepared in sterile form, and when intended for delivery by other than oral administration generally may be isotonic. All compositions may optionally contain excipients such as those set forth in the Rowe et al, Handbook of Pharmaceutical Excipients, 6 th edition, American Pharmacists Association, 2009. Excipients can include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid and the like.
  • the composition is provided as a solid dosage form, including a solid oral dosage form.
  • compositions include those suitable for various administration routes, including oral administration.
  • the compositions may be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient (e.g., a compound of the present disclosure or a pharmaceutical salt thereof) with one or more pharmaceutically acceptable excipients.
  • the compositions may be prepared by uniformly and intimately bringing into association the active ingredient with liquid excipients or finely divided solid excipients or both, and then, if necessary, shaping the product. Techniques and formulations generally are found in Remington: The Science and Practice of Pharmacy, 21 st Edition, Lippincott Williams and Wilkins, Philadelphia, Pa., 2006.
  • compositions described herein that are suitable for oral administration may be presented as discrete units (a unit dosage form) including but not limited to capsules, cachets or tablets each containing a predetermined amount of the active ingredient.
  • the pharmaceutical composition is a tablet.
  • phrases disclosed herein comprise one or more compounds disclosed herein, or a pharmaceutically acceptable salt thereof, together with a
  • phrases containing the active ingredient may be in any form suitable for the intended method of administration.
  • tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs may be prepared.
  • Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more excipients including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation. Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for manufacture of tablets are acceptable.
  • excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as cellulose, microcrystalline cellulose, starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.
  • inert diluents such as calcium or sodium carbonate, lactose, lactose monohydrate, croscarmel
  • a dosage form for oral administration to humans may contain approximately 1 to 1000 mg of active material formulated with an appropriate and convenient amount of a pharmaceutically acceptable excipient.
  • the pharmaceutically acceptable excipient varies from about 5 to about 95% of the total compositions (weight:weight).
  • compositions comprising a compound of the present disclosure do not contain an agent that affects the rate at which the active ingredient is metabolized.
  • compositions comprising a compound of the present disclosure in one aspect do not comprise an agent that would affect (e.g., slow, hinder or retard) the metabolism of a compound of the present disclosure or any other active ingredient administered separately, sequentially or simultaneously with a compound of the present disclosure.
  • any of the methods, kits, articles of manufacture and the like detailed herein in one aspect do not comprise an agent that would affect (e.g., slow, hinder or retard) the metabolism of a compound of the present disclosure or any other active ingredient administered separately, sequentially or
  • the disclosure further includes a pharmaceutical composition as described above for use in modulating STING adaptor protein activity, to induce STING-dependent production of type I interferons, cytokines or chemokines.
  • the disclosure further includes a pharmaceutical composition as described above for use in treating or preventing an infectious disease, such as a viral infection, e.g., infection caused by hepatitis B or hepatitis C virus, cancer, or an inflammatory disease, e.g., allergy, rhinitis, or asthma.
  • an infectious disease such as a viral infection, e.g., infection caused by hepatitis B or hepatitis C virus, cancer, or an inflammatory disease, e.g., allergy, rhinitis, or asthma.
  • the disclosure further includes a compound of the present disclosure for administration as a single active ingredient of a pharmaceutically acceptable composition which can be prepared by conventional methods known in the art, for example by binding the active ingredient to a pharmaceutically acceptable, therapeutically inert organic and/or inorganic carrier or excipient, or by mixing therewith.
  • Another possibility is the use of a compound of the present disclosure as a second or other active ingredient having a synergistic effect with other active ingredients in known drugs, or administration of the compound of the present disclosure together with such drugs.
  • the compound of the present disclosure may also be used in the form of a prodrug or other suitably modfied form which releases the active ingredient in vivo.
  • a method of treating a disease or disorder comprises administering to a human or animal in need thereof a therapeutically effective amount of a compound of the present disclosure, or a tautomer, enantiomer, hydrate, solvate, or pharmaceutically acceptable salt thereof.
  • a method of modulating, e.g., increasing, the activity of STING adaptor protein comprises administering an effective amount of a compound of the present disclosure, or a tautomer, enantiomer, hydrate, solvate, or pharmaceutically acceptable salt, thereof.
  • Modulation, e.g., activation, of the STING adaptor protein can occur in a cell, for example, by contacting the cell with an effective amount of the compound of the present disclosure, or a tautomer, enantiomer, hydrate, solvate, or pharmaceutically acceptable salt thereof. Contacting the cell can occur in vitro or in vivo. Modulation of the activity of the STING adaptor protein can be determined by measuring any one of a number of downstream biochemical signals affected by the protein.
  • the Stimulator of interferon genes (STING) adaptor protein also known as STING, STING protein, transmembrane protein 173 (TMEM173), MPYS, mediator of IRF3 activation (MGGA), or endoplasmic reticulum interferon stimulator (ERIS), is a protein that in humans is encoded by the TMEM173 gene (UniProt code Q86WV6; NCBI Reference
  • STING adaptor protein is believed to function as both a direct cytosolic DNA sensor (CDS) and an adaptor protein in Type I interferon signaling through different molecular mechanisms.
  • CDS direct cytosolic DNA sensor
  • STING adaptor protein has been shown to activate downstream transcription factors STAT6 and IRF3 through TBK1, and NF-KB through IKKb, which can effect an antiviral response or innate immune response against an intracellular pathogen.
  • STING adaptor protein plays a role in innate immunity by inducing type I interferon production when cells are infected with intracellular pathogens, such as viruses, mycobacteria and intracellular parasites.
  • Type I interferon mediated by STING adaptor protein, protects infected cells and nearby cells from local infection by autocrine and paracrine signaling.
  • STING adaptor protein in turn activates protein kinase TBK1, which subsequently activates downstream transcription factors NF-kB and IRF-3. Activation of STING adaptor protein ultimately is believed to result in the release of type I and III interferons as well as a variety of cytokines and chemokines such as IL-6, TNF-a and INF-g.
  • induction of a STING adaptor protein-dependent type I interferon, cytokine or chemokine in a human or animal results in the activation of one or more of NF-KB, IRF-3, a type I interferon, a type III interferon, IL-6, TNF-a, and INF-g in said human or animal.
  • a method of preventing or treating a disease or condition responsive to the modulation, e.g., activation, of STING adaptor protein comprising administering to a human or animal in need thereof a therapeutically effective amount of a compound of the present disclosure, or a tautomer, enantiomer, hydrate, solvate, or pharmaceutically acceptable salt thereof.
  • a method of inducing a STING adaptor protein-dependent type I interferon, cytokine or chemokine in a human or animal comprising administering a therapeutically effective amount of a compound of the present disclosure, or a tautomer, enantiomer, hydrate, solvate, or pharmaceutically acceptable salt thereof.
  • a method of treating or preventing an infectious disease, e.g., a viral infection comprising administering to a human or animal in need thereof a
  • Infectious disease encompasses diseases arising from the presence of a foreign microorganism in the body. It includes viral infections, bacterial infections (such as those caused by gram positive and gram negative bacteria), fungal infections, and those caused by other microorganisms, such as protozoa. In some embodiments, the infectious disease is a viral infection.
  • Viral infections that can be treated or prevented by the methods of the present disclosure can be any infection caused by a virus, e.g., a virus from the any of the following virus families: Adenoviridae, such as adenoviruses; Calciviridae; Filoviridae, such as ebola; Flavtviridae, e.g., dengue fever, West Nile virus, Zika virus, encephalitis, hepatitis C, and yellow fever; Hepadnaviridae, e.g., hepatitis B; Herpesviridae, e.g., herpes simplex virus (HSV) 1 and 2, varicella zoster virus, cytomegalovirus (CMV), and herpes virus;
  • Adenoviridae such as adenoviruses
  • Calciviridae such as ebola
  • Flavtviridae e.g., dengue fever, West Nile virus, Zika
  • Parvoviridae parvoviruses
  • Paramyxoviridae e.g., parainfluenza, mumps, and measles
  • Papovaviridae papilloma viruses, polyoma viruses
  • Picomaviridae e.g., polio, hepatitis A virus
  • enteroviruses human Coxsackie viruses, rhinoviruses, and echoviruses
  • Poxviridae e.g., variola viruses, vaccinia viruses, and pox viruses
  • Retroviridae e.g., human
  • the viral infection is a hepatitis B or hepatitis C infection.
  • a method of treating or preventing an inflammatory disease comprising administering to a human or animal in need thereof a therapeutically effective amount of a compound of of the present disclosure, or a tautomer, enantiomer, hydrate, solvate, or pharmaceutically acceptable salt thereof.
  • Inflammatory diseases include but are not limited to allergy, rhinitis, and asthma.
  • a method of treating or preventing cancer comprising administering to a human or animal in need thereof a therapeutically effective amount of a compound of of the present disclosure, or a tautomer, enantiomer, hydrate, solvate, or pharmaceutically acceptable salt thereof.
  • Cancers that can be treated or prevented by the methods of the disclosure include solid tumors, leukemias, and lymphomas, including but not limited to adrenal cancer, bladder cancer, bone cancer, brain cancer, breast cancer, colon cancer, colorectal cancer, eye cancer, gastric cancer, head-and-neck cancer, kidney cancer such as renal cell carcinoma, liver cancer, lung cancer such as non-small cell lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer such as squamous cell carcinoma and melanoma, thyroid cancer, uterine cancer, vaginal cancer, leukemia such as myeloid leukemia and lymphoblastic leukemia, and myeloma such as multiple myeloma.
  • the cancer can be naive, or relapsed and/or refractory.
  • a method of enhancing the efficacy of a vaccine comprising administering to a human or animal in need thereof a therapeutically effective amount of a compound of the present disclosure, or a tautomer, enantiomer, hydrate, solvate, or pharmaceutically acceptable salt thereof.
  • the disclosure includes a compound of the present disclosure, or a tautomer, enantiomer, hydrate, solvate, or pharmaceutically acceptable salt thereof for use as a medicament in a human or animal.
  • the disclosure further includes a compound of the present disclosure, or a tautomer, enantiomer, or pharmaceutically acceptable salt thereof for use in modulating, e.g., increasing, the activity of STING adaptor protein.
  • the disclosure further includes a compound of the present disclosure, or a tautomer, enantiomer, hydrate, solvate, or pharmaceutically acceptable salt thereof for use in the prevention or treatment of a disease or condition in a human or animal responsive to the modulation, e.g., activation, of the STING adaptor protein.
  • the disclosure further includes a compound of the present disclosure, or a tautomer, enantiomer, or pharmaceutically acceptable salt thereof alone or in combination with one or more therapeutically active substances, for use in STING dependent induction of a type I interferon, cytokine or chemokine in a human or animal.
  • the disclosure further includes a compound of the present disclosure, or a tautomer, enantiomer, hydrate, solvate, or pharmaceutically acceptable salt thereof alone or in combination with one or more therapeutically active agents for use in the treatment or prevention of an infectious disease in a human or animal.
  • the disclosure further includes a compound of the present disclosure, or a tautomer, enantiomer, hydrate, solvate, or pharmaceutically acceptable salt thereof alone or in combination with one or more therapeutically active substances, for use in the treatment or prevention of an infectious disease, e.g., a viral infection, e.g., infection caused by hepatitis B virus or HIV, in a human or animal.
  • an infectious disease e.g., a viral infection, e.g., infection caused by hepatitis B virus or HIV
  • the disclosure further includes a compound of the present disclosure, or a tautomer, enantiomer, hydrate, solvate, or pharmaceutically acceptable salt thereof alone or in combination with one or more therapeutically active agents, for use in the treatment or prevention of a cancer in a human or animal.
  • the disclosure further includes a compound of the present disclosure, or a tautomer, enantiomer, hydrate, solvate, or pharmaceutically acceptable salt thereof for use in enhancing vaccine efficacy in a human or animal.
  • the disclosure further includes a pharmaceutical composition for use in modulating STING adaptor protein activity, to induce STING-dependent production of a type I interferon, cytokine or chemokine in a human or animal.
  • the disclosure further includes a pharmaceutical composition for use in treating or preventing viral infection, cancer, or an inflammatory disease in a human or animal.
  • the disclosure further includes the use of a compound of the present disclosure, or a tautomer, enantiomer, hydrate, solvate, or pharmaceutically acceptable salt thereof for the production of a medicament for the treatment or prevention of viral infection, cancer, or an inflammatory disease.
  • the compounds of the present disclosure can be administered by any route appropriate to the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), transdermal, vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intratumoral, intradermal, intrathecal and epidural), and the like. It will be appreciated that the preferred route may vary with for example the condition of the recipient. An advantage of certain compounds disclosed herein is that they are orally bioavailable and can be dosed orally.
  • a compound of the present disclosure may be administered to an individual in accordance with an effective dosing regimen for a desired period of time or duration, such as at least about one month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or longer.
  • the compound is administered on a daily or intermittent schedule for the duration of the individual's life.
  • the dosage or dosing frequency of a compound of the present disclosure may be adjusted over the course of the treatment, based on the judgment of the administering physician.
  • the compound may be administered to an individual (e.g., a human) in an effective amount. In certain embodiments, the compound is administered once daily.
  • the compound can be administered by any useful route and means, such as by oral or parenteral (e.g., intravenous) administration.
  • Therapeutically effective amounts of the compound may include from about 0.00001 mg/kg body weight per day to about 10 mg/kg body weight per day, such as from about 0.0001 mg/kg body weight per day to about 10 mg/kg body weight per day, or such as from about 0.001 mg/kg body weight per day to about 1 mg/kg body weight per day, or such as from about 0.01 mg/kg body weight per day to about 1 mg/kg body weight per day, or such as from about 0.05 mg/kg body weight per day to about 0.5 mg/kg body weight per day, or such as from about 0.3 mg to about 30 mg per day, or such as from about 30 mg to about 300 mg per day.
  • a compound of the present disclosure may be combined with one or more additional therapeutic agents in any dosage amount of the compound of the present disclosure (e.g., from 1 mg to 1000 mg of compound).
  • Therapeutically effective amounts may include from about 1 mg per dose to about 1000 mg per dose, such as from about 50 mg per dose to about 500 mg per dose, or such as from about 100 mg per dose to about 400 mg per dose, or such as from about 150 mg per dose to about 350 mg per dose, or such as from about 200 mg per dose to about 300 mg per dose.
  • Other therapeutically effective amounts of the compound of the present disclosure are about 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350,
  • a single dose can be administered hourly, daily, or weekly. For example, a single dose can be administered once every 1 hour, 2, 3, 4, 6, 8, 12, 16 or once every 24 hours. A single dose can also be administered once every 1 day, 2, 3, 4, 5, 6, or once every 7 days. A single dose can also be administered once every 1 week, 2, 3, or once every 4 weeks. In certain embodiments, a single dose can be administered once every week. A single dose can also be administered once every month.
  • the frequency of dosage of the compound of the present disclosure are will be determined by the needs of the individual patient and can be, for example, once per day or twice, or more times, per day. Administration of the compound continues for as long as necessary to treat or to prevent the disease.
  • a compound can be administered to a human being infected with a virus, e.g., hepatitis B vims, for a period of from 20 days to 180 days or, for example, for a period of from 20 days to 90 days or, for example, for a period of from 30 days to 60 days.
  • a virus e.g., hepatitis B vims
  • Administration can be intermittent, with a period of several or more days during which a patient receives a daily dose of the compound of the present disclosure followed by a period of several or more days during which a patient does not receive a daily dose of the compound.
  • a patient can receive a dose of the compound every other day, or three times per week.
  • a patient can receive a dose of the compound each day for a period of from 1 to 14 days, followed by a period of 7 to 21 days during which the patient does not receive a dose of the compound, followed by a subsequent period (e.g., from 1 to 14 days) during which the patient again receives a daily dose of the compound.
  • Alternating periods of administration of the compound, followed by non- administration of the compound can be repeated as clinically required to treat the patient.
  • compositions comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents, and a pharmaceutically acceptable excipient are provided.
  • kits comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents are provided.
  • one or more e.g., one, two, three, four, one or two, one to three, or one to four
  • a pharmaceutically acceptable salt thereof is combined with one, two, three, four or more additional therapeutic agents.
  • a compound of the present disclosure, or a pharmaceutically acceptable salt thereof is combined with two additional therapeutic agents.
  • a compound of the present disclosure, or a pharmaceutically acceptable salt thereof is combined with three additional therapeutic agents.
  • a compound of the present disclosure, or a pharmaceutically acceptable salt thereof is combined with four additional therapeutic agents.
  • the one, two, three, four or more additional therapeutic agents can be different therapeutic agents selected from the same class of therapeutic agents, and/or they can be selected from different classes of therapeutic agents.
  • the components of the composition are administered as a simultaneous or sequential regimen.
  • the combination may be administered in two or more administrations.
  • a compound of the present disclosure is combined with one or more additional therapeutic agents in a unitary dosage form for simultaneous
  • administration to a patient for example as a solid dosage form for oral administration.
  • a compound of the present disclosure is co-administered with one or more additional therapeutic agents.
  • a method for treating or preventing an infectious disease, cancer, or an inflammatory disease in a human having or at risk of having the disease comprising administering to the human a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents.
  • a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents.
  • a method for treating an infectious disease, cancer, or an inflammatory disease in a human having or at risk of having the disease comprising administering to the human a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents.
  • a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents.
  • the present disclosure provides a method for treating a viral infection, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents which are suitable for treating the viral infection.
  • the viral infection is a hepatitis B infection.
  • the viral infection is a HIV infection.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with one, two, three, four, or more additional therapeutic agents.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with two additional therapeutic agents. In other embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with three additional therapeutic agents. In further embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with four additional therapeutic agents.
  • the one, two, three, four, or more additional therapeutic agents can be different therapeutic agents selected from the same class of therapeutic agents, and/or they can be selected from different classes of therapeutic agents. Administration of Combination Theraov
  • a compound disclosed herein is administered with one or more additional therapeutic agents.
  • Co-administration of a compound disclosed herein with one or more additional therapeutic agents generally refers to simultaneous or sequential administration of a compound disclosed herein and one or more additional therapeutic agents, such that therapeutically effective amounts of the compound disclosed herein and the one or more additional therapeutic agents are both present in the body of the subject.
  • the combination may be administered in two or more
  • Co-administration of a compound disclosed herein with one or more additional therapeutic agents generally refers to simultaneous or sequential administration of a compound disclosed herein and one or more additional therapeutic agents, such that therapeutically effective amounts of each agent are present in the body of the patient.
  • a compound as disclosed herein may be combined with one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents in any dosage amount of the compound of Formula I (e.g., from 10 mg to 1000 mg of compound).
  • one or more e.g., one, two, three, four, one or two, one to three, or one to four
  • additional therapeutic agents in any dosage amount of the compound of Formula I (e.g., from 10 mg to 1000 mg of compound).
  • Co-administration includes administration of unit dosages of the compounds disclosed herein before or after administration of unit dosages of one or more additional therapeutic agents.
  • the compound disclosed herein may be administered within seconds, minutes, or hours of the administration of one or more additional therapeutic agents.
  • a unit dose of a compound disclosed herein is administered first, followed within seconds or minutes by administration of a unit dose of one or more additional therapeutic agents.
  • a unit dose of one or more additional therapeutic agents is administered first, followed by administration of a unit dose of a compound disclosed herein within seconds or minutes.
  • a unit dose of a compound disclosed herein is administered first, followed, after a period of hours (e.g., 1-12 hours), by administration of a unit dose of one or more additional therapeutic agents.
  • a unit dose of one or more additional therapeutic agents is administered first, followed, after a period of hours (e.g., 1-12 hours), by administration of a unit dose of a compound disclosed herein.
  • a compound of the present disclosure is combined with one or more additional therapeutic agents in a unitary dosage form for simultaneous
  • administration to a subject for example as a solid dosage form for oral administration.
  • a compound of the present disclosure is formulated as a tablet, which may optionally contain one or more other compounds useful for treating the disease being treated.
  • the tablet can contain another active ingredient for treating a viral disease, e.g., hepatitis B vims or HIV.
  • such tablets are suitable for once daily dosing.
  • compositions comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents, and a pharmaceutically acceptable carrier, diluent, or excipient are provided.
  • kits comprising a compound disclosed herein, or a
  • pharmaceutically acceptable salt thereof in combination with one or more (e.g., one, two, three, four, one or two, or one to three, or one to four) additional therapeutic agents are provided.
  • one or more e.g., one, two, three, four, one or two, or one to three, or one to four
  • the compounds described herein may be used or combined with one or more of a antiviral agents including abacavir, aciclovir, adefovir, amantadine, amprenavir, arbidol, atazanavir, artipla, brivudine, cidofovir, combivir, edoxudine, efavirenz, emtricitabine, enfuvirtide, entecavir, fomvirsen, fosamprenavir, foscamet, fosfonet, ganciclovir, gardasil, ibacitabine, immunovir, idoxuridine, imiquimod, indinavir, inosine, integrase inhibitors, interferons, including interferon type III, interferon type II, interferon type I, lamivudine, lopinavir, loviride, MK-0518, maraviroc, moroxydine, nelfin
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with 5-30 mg tenofovir alafenamide fiunarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with 5-10; 5-15; 5-20; 5-25; 25-30; 20-30; 15-30; or 10-30 mg tenofovir alafenamide fiunarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide.
  • a compound as disclosed herein may be combined with the agents provided herein in any dosage amount of the compound (e.g., from 50 mg to 500 mg of compound) the same as if each combination of dosages were specifically and individually listed.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with 100-400 mg tenofovir disoproxil fiunarate, tenofovir disoproxil hemifiunarate, or tenofovir disoproxil.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with 100-150; 100-200, 100-250; 100-300; 100-350; 150-200; 150-250; 150-300; 150-350; 150- 400; 200-250; 200-300; 200-350; 200-400; 250-350; 250-400; 350-400 or 300-400 mg tenofovir disoproxil fiunarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with 300 mg tenofovir disoproxil fiunarate, tenofovir disoproxil hemifiunarate, or tenofovir disoproxil. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 250 mg tenofovir disoproxil fiunarate, tenofovir disoproxil hemifiunarate, or tenofovir disoproxil.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with 150 mg tenofovir disoproxil fiunarate, tenofovir disoproxil hemifiunarate, or tenofovir disoproxil.
  • a compound as disclosed herein e.g., a compound of Formula I
  • HIV Combination Therapy 50 mg to 500 mg of compound) the same as if each combination of dosages were specifically and individually listed.
  • a method for treating or preventing an HIV infection in a human or animal having or at risk of having the infection comprising administering to the human or animal a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents.
  • a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents.
  • a method for treating an HIV infection in a human or animal having or at risk of having the infection comprising administering to the human or animal a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents.
  • a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents.
  • the present disclosure provides a method for treating an HIV infection, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents which are suitable for treating an HIV infection.
  • the compounds disclosed herein are formulated as a tablet, which may optionally contain one or more other compounds useful for treating HIV.
  • the tablet can contain another active ingredient for treating HIV, such as HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, pharmacokinetic enhancers, and combinations thereof.
  • such tablets are suitable for once daily dosing.
  • the additional therapeutic agent is selected from the group consisting of combination drags for HIV, other drags for treating HIV, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latency reversing agents, capsid inhibitors, immune-based therapies, PI3K inhibitors, HIV antibodies, and bispecific antibodies, and“antibody-like” therapeutic proteins, and combinations thereof.
  • combination drags include ATRIPLA ® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); COMPLERA ® (EVIPLERA ® ; rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD ® (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); TRUVADA ® (tenofovir disoproxil fumarate and emtricitabine; TDF+FTC); DESCOVY® (tenofovir alafenamide and emtricitabine); ODEFSEY® (tenofovir alafenamide, emtricitabine, and rilpivirine); GENVOYA® (tenofovir alafenamide, emtricitabine, cobicistat, and elvitegravir);
  • EPZICOM ® (LIVEXA ® ; abacavir sulfate and lamivudine; ABC+3TC);
  • KALETRA ® (ALUVIA ® ; lopinavir and ritonavir); TRIUMEQ ® (dolutegravir, abacavir, and lamivudine); TRIZIVIR ® (abacavir sulfate, zidovudine, and lamivudine; ABC+AZT+3TC); atazanavir and cobicistat; atazanavir sulfate and cobicistat; atazanavir sulfate and ritonavir; darunavir and cobicistat; dolutegravir and rilpivirine; dolutegravir and rilpivirine
  • dolutegravir dolutegravir, abacavir sulfate, and lamivudine; lamivudine, nevirapine, and zidovudine; raltegravir and lamivudine; doravirine, lamivudine, and tenofovir disoproxil fiimarate; doravirine, lamivudine, and tenofovir disoproxil; dolutegravir + lamivudine, lamivudine + abacavir + zidovudine, lamivudine + abacavir, lamivudine + tenofovir disoproxil fiimarate, lamivudine + zidovudine + nevirapine, lopinavir + ritonavir, lopinavir + ritonavir + abacavir + lamivudine, lopinavir + r
  • HIV Protease Inhibitors examples include amprenavir, atazanavir, brecanavir, darunavir, fosamprenavir, fosamprenavir calcium, indinavir, indinavir sulfate, lopinavir, nelfinavir, nelfinavir mesylate, ritonavir, saquinavir, saquinavir mesylate, tipranavir, DG-17, TMB-657 (PPL- 100), T-169, BL-008, and TMC-310911.
  • HIV Reverse Transcriptase Inhibitors examples include dapivirine, delavirdine, delavirdine mesylate, doravirine, efavirenz, etravirine, lentinan, nevirapine, rilpivirine, ACC-007, AIC-292, KM-023, PC-1005, and VM-
  • HIV nucleoside or nucleotide inhibitors of reverse transcriptase include adefovir, adefovir dipivoxil, azvudine, emtricitabine, tenofovir, tenofovir alafenamide, tenofovir alafenamide fiimarate, tenofovir alafenamide hemifiimarate, tenofovir disoproxil, tenofovir disoproxil fiimarate, tenofovir disoproxil hemifiimarate, VIDEX ® and VIDEX EC ® (didanosine, ddl), abacavir, abacavir sulfate, alovudine, apricitabine, censavudine, didanosine, elvucitabine, festinavir, fosalvudine tidoxil, CMX-157, dapivirine
  • HIV integrase inhibitors include elvitegravir, curcumin, derivatives of curcumin, chicoric acid, derivatives of chicoric acid, 3,5-dicaffeoylquinic acid, derivatives of 3,5-dicaffeoylquinic acid, aurintricarboxylic acid, derivatives of aurintricarboxylic acid, caffeic acid phenethyl ester, derivatives of caffeic acid phenethyl ester, tyrphostin, derivatives oftyrphostin, quercetin, derivatives of quercetin, raltegravir, dolutegravir, JTK-351, bictegravir, AVX-15567, cabotegravir (long-acting injectable), diketo quinolin-4-1 derivatives, integrase-LEDGF inhibitor, ledgins, M-522, M-532, NSC-310217, NSC- 371056, NSC-48240, NSC-
  • NICKI HIV non-catalytic site, or allosteric, integrase inhibitors
  • gp41 inhibitors include albuvirtide, enfuvirtide, BMS-986197, enfuvirtide biobetter, enfuvirtide biosimilar, HIV-1 fusion inhibitors (P26-Bapc), ITV-1, ITV-2, ITV-3, ITV-4, PIE-12 trimer and sifuvirtide.
  • CXCR4 inhibitors include plerixafor, ALT-1188, N15 peptide, and vMIP (Haimipu).
  • HIV Maturation Inhibitors [0183] Examples of HIV maturation inhibitors include BMS-955176 and GSK-2838232.
  • PKC activators include indolactam, prostratin, ingenol B, and DAG- lactones.
  • capsid inhibitors include capsid polymerization inhibitors or capsid disrupting compounds, HIV nucleocapsid p7 (NCp7) inhibitors such as azodicarbonamide, HIV p24 capsid protein inhibitors, AVI-621, AVI-101, AVI-201, AVI-301, and AVI-CAN1- 15 series;
  • NCp7 HIV nucleocapsid p7
  • hydroxychloroquine hydroxychloroquine
  • proleukin aldesleukin, IL-2
  • interferon alfa interferon alfa-2b
  • interferon alfa-n3 pegylated interferon alfa
  • interferon gamma hydroxyurea
  • mycophenolate mofetil MPA
  • mycophenolate mofetil MMF
  • ribavirin ribavirin
  • rintatolimod polymer polyethyleneimine (PEI); gepon; rintatolimod; IL-12; WF-10; VGV-1; MOR-22; BMS-936559; CYT-107, interleukin- 15/Fc fusion protein, normferon,
  • peginterferon alfa-2a peginterferon alfa-2b
  • recombinant interleukin-15 RPI-MN
  • GS-9620 STING modulators
  • RIG-I modulators RIG-I modulators
  • NOD2 modulators and IR-103.
  • Phosphatidylinositol 3-kinase (PI3K) Inhibitors include idelalisib, alpelisib, buparlisib, CAI orotate, copanlisib, duvelisib, gedatolisib, neratinib, panulisib, perifosine, pictilisib, pilaralisib, puquitinib mesylate, rigosertib, rigosertib sodium, sonolisib, taselisib, AMG-319, AZD-8186, BAY-1082439, CLR-1401, CLR-457, CUDC-907, DS-7423, EN-3342, GSK-2126458, GSK- 2269577, GSK-2636771, INCB-040093, LY-3023414, MLN-1117, PQR-309,
  • HIV Antibodies, Bispecific Antibodies, and“Antibody-like” Therapeutic Proteins include DARTs ® , DUOBODIES ® , BITES ® , XmAbs ® , TandAbs ® , Fab derivatives, bnABs (broadly neutralizing HIV-1 antibodies), BMS-936559, TMB-360, and those targeting HIV gp120 or gp41, antibody-Recruiting Molecules targeting HIV, anti-CD63 monoclonal antibodies, anti-GB virus C antibodies, anti-GP120/CD4, CCR5 bispecific antibodies, anti- nef single domain antibodies, anti -Rev antibody, camelid derived anti-CD 18 antibodies, camelid-derived anti-ICAM-1 antibodies, DCVax-001, gpl40 targeted antibodies, gp41- based HIV therapeutic antibodies, human recombinant mAbs (PGT-121), ibal
  • HIV bispecific antibodies include MGD014.
  • Examples of pharmacokinetic enhancers include cobicistat and ritonavir.
  • TBC-M4 therapeutic HIV vaccine, UBI HIV gp120, Vacc-4x + romidepsin, variant gp120 polypeptide vaccine, rAd5 gag-pol env A/B/C vaccine, DNA.HTI and MVA.HTI.
  • HIV therapeutic agents include the compounds disclosed in WO 2004/096286 (Gilead Sciences), WO 2006/015261 (Gilead Sciences), WO 2006/110157 (Gilead Sciences), WO 2012/003497 (Gilead Sciences), WO 2012/003498 (Gilead Sciences), WO 2012/145728 (Gilead Sciences), WO 2013/006738 (Gilead Sciences), WO 2013/159064 (Gilead Sciences), WO 2014/100323 (Gilead Sciences), US 2013/0165489 (University of Pennsylvania), US 2014/0221378 (Japan Tobacco), US 2014/0221380 (Japan Tobacco), WO 2009/062285 (Boehringer Ingelheim), WO 2010/130034 (Boehringer Ingelheim), WO 2010/130034 (Boehringer Ingelheim), WO 2010/130034 (Boehringer Ingelheim), WO 2010/130034 (Boehringer Ingelheim), WO 2010/1300
  • Examples of other drugs for treating HIV include acemannan, alisporivir, BanLec, deferiprone, Gamimune, metenkefalin, naltrexone, Prolastin, REP 9, RPI-MN, VSSP, Hlviral, SB-728-T, 1,5-dicaffeoylquinic acid, rHIV7-shl-TAR-CCR5RZ, AAV-eCD4-Ig gene therapy, MazF gene therapy, BlockAide, ABX-464, AG-1105, APH-0812, BIT-225, CYT-107, HGTV-43, HPH-116, HS-10234, IMO-3100, IND-02, MK-1376, MK-8507, MK- 8591, NOV-205, PA-1050040 (PA-040), PGN-007, SCY-635, SB-9200, SCB-719, TR-452, TEV-90110, TEV-90112, TEV-90111,
  • Gene Therapy and Cell Therapy include the genetic modification to silence a gene; genetic approaches to directly kill the infected cells; the infusion of immune cells designed to replace most of the subject's own immune system to enhance the immune response to infected cells, or activate the subject's own immune system to kill infected cells, or find and kill the infected cells; genetic approaches to modify cellular activity to further alter endogenous immune responsiveness against the infection.
  • Examples of dendritic cell therapy include AGS-004.
  • Examples of gene editing systems include a CRISPR/Cas9 system, a zinc finger nuclease system, a TALEN system, a homing endonucleases system, and a meganuclease system.
  • HIV targeting CRISPR/Cas9 systems examples include EBT101.
  • HIV CAR-T examples include VC-CAR-T.
  • TCR-T cell therapy includes T cells engineered to target HIV derived peptides present on the surface of virus-infected cells.
  • additional therapeutic agents fisted above may be included in more than one of the classes fisted above. The particular classes are not intended to limit the functionality of those compounds fisted in those classes.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase and an HIV non-nucleoside inhibitor of reverse transcriptase.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, and an HIV protease inhibiting compound.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV non-nucleoside inhibitor of reverse transcriptase, and a pharmacokinetic enhancer.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with at least one HIV nucleoside inhibitor of reverse transcriptase, an integrase inhibitor, and a pharmacokinetic enhancer.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with two HIV nucleoside or nucleotide inhibitors of reverse transcriptase.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with one, two, three, four or more additional therapeutic agents selected from ATRIPLA ® (efavirenz, tenofovir disoproxil fumarate, and
  • emtricitabine COMPLERA ® (EVIPLERA ® ; rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD ® (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); TRUVADA ® (tenofovir disoproxil fumarate and emtricitabine; TDF +FTC); DESCOVY® (tenofovir alafenamide and emtricitabine); ODEFSEY® (tenofovir alafenamide, emtricitabine, and rilpivirine); GENVOYA® (tenofovir alafenamide, emtricitabine, cobicistat, and elvitegravir); BIKTARVY® (bictegravir, emtricitabine, tenofovir alafenamide); ade
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, tenofovir alafenamide hemifumarate, or bictegravir.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with a first additional therapeutic agent selected from the group consisting of tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, tenofovir alafenamide hemifumarate, and bictegravir and a second additional therapeutic agent, wherein the second additional therapeutic agent is emtricitabine.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with 5-30 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide, and 200 mg emtricitabine.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with 5-10, 5-15, 5-20, 5-25, 25-30, 20-30, 15-30, or 10-30 mg tenofovir alafenamide fiunarate, tenofovir alafenamide hemifiunarate, or tenofovir alafenamide, and 200 mg emtricitabine.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with 200-400 mg tenofovir disoproxil fiunarate, tenofovir disoproxil hemifiunarate, or tenofovir disoproxil, and 200 mg emtricitabine.
  • a compound as disclosed herein may be combined with the agents provided herein in any dosage amount of the compound (e.g., from 1 mg to 500 mg of compound) the same as if each combination of dosages were specifically and individually listed.
  • a method for treating an HBV infection in a human having or at risk of having the infection comprising administering to the human a therapeutically effective amount of a compound disclosed herein, or a
  • pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents.
  • one or more e.g., one, two, three, four, one or two, one to three, or one to four
  • the compounds described herein may be used or combined with one or more of a chemotherapeutic agent, an immunomodulator, an immunotherapeutic agent, a therapeutic antibody, a therapeutic vaccine, a bispecific antibody and“antibody-like” therapeutic protein (such as DARTs®, Duobodies®, Bites®, XmAbs®, TandAbs ®, Fab derivatives), an antibody-drug conjugate (ADC), gene modifiers or gene editors (such as CRISPR Cas9, zinc finger nucleases, homing endonucleases, synthetic nucleases , TALENs), cell therapies such as CAR-T (chimeric antigen receptor T-cell ), and TCR-T (an engineered T cell receptor) agent or any combination thereof.
  • a chemotherapeutic agent such as DARTs®, Duobodies®, Bites®, XmAbs®, TandAbs ®, Fab derivatives
  • ADC antibody-drug conjugate
  • gene modifiers or gene editors such
  • a compound of Formula (I) is formulated as a tablet, which may optionally contain one or more other compounds useful for treating HBV.
  • the tablet can contain another active ingredient for treating HBV, such as 3- dioxygenase (IDO) inhibitors, Apolipoprotein A1 modulator, arginase inhibitors, B- and T- lymphocyte attenuator inhibitors, Bruton's tyrosine kinase (BTK) inhibitors, CCR2 chemokine antagonist, CD137 inhibitors, CD160 inhibitors, CD305 inhibitors, CD4 agonist and modulator, compounds targeting HBcAg, compounds targeting hepatitis B core antigen (HBcAg), core protein allosteric modulators, covalently closed circular DNA (cccDNA) inhibitors, cyclophilin inhibitors, cytotoxic T-lymphocyte-associated protein 4 (ipi4) inhibitors, DNA polymerase inhibitor, Endonuclease modulator, epigenetic
  • IDO 3- dioxygenase
  • combination drugs for the treatment of HBV include TRUVADA ® (tenofovir disoproxil fumarate and emtricitabine); ABX-203, lamivudine, and PEG-IFN- alpha; ABX-203 adefovir, and PEG-IFNalpha; and INO-1800 (INO-9112 and RG7944).
  • HBV vaccines include both prophylactic and therapeutic vaccines. Examples of
  • HBV prophylactic vaccines include Vaxelis, Hexaxim, Heplisav, Mosquirix, DTwP-HBV vaccine, Bio-Hep-B, D/T/P/HBV/M (LBVP-0101; LBVW-0101), DTwP-Hepb-Hib-IPV vaccine, Heberpenta L, DTwP-HepB-Hib, V-419, CVI-HBV-001, Tetrabhay, hepatitis B prophylactic vaccine (Advax Super D), Hepatrol-07, GSK-223192A, ENGERIX B ® , recombinant hepatitis B vaccine (intramuscular, Kangtai Biological Products), recombinant hepatitis B vaccine (Hansenual polymorpha yeast, intramuscular, Huai an Biological Engineering), recombinant hepatitis B surface antigen vaccine, Bimmugen, Euforavac, Eutravac, anrix-DT
  • HBV DNA polymerase inhibitors include adefovir (HEPSERA ® ), emtricitabine (EMTRIVA ® ), tenofovir disoproxil fiunarate (VIREAD ® ), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fiunarate, tenofovir alafenamide hemifiunarate, tenofovir dipivoxil , tenofovir dipivoxil fiunarate, tenofovir octadecyloxyethyl ester, CMX-157, besifovir, entecavir (BARACLUDE ® ), entecavir maleate, telbivudine (TYZEKA ® ), filocilovir, pradefovir, clevudine, ribavirin, lamivudine
  • TLR Toll-like Receptor
  • TLR modulators include modulators of TLR 1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12, and TLR13.
  • TLR3 modulators include rintatolimod, poly-ICLC, RIBOXXON ® , Apoxxim, RIBOXXIM ® , IPH-33, MCT- 465, MCT-475, and ND-1.1.
  • TLR7 modulators include GS-9620, GSK-2245035, imiquimod, resiquimod, DSR-6434, DSP-3025, IMO-4200, MCT-465, MEDI-9197, 3M-051, SB-9922, 3M-052, Limtop, D, telratolimod, SP-0509, TMX-30X, TMX-202, RG-7863, RG-7795, LHC-165, RG-7854, and the compounds disclosed in US20100143301 (Gilead Sciences), US20110098248 (Gilead Sciences), and US20090047249 (Gilead Sciences).
  • WO2017216054 (Roche),WO2017202703 (Roche), WO2017184735 (IFM Therapeutics), WO2017184746 (IFM Therapeutics), WO2015088045 (Takeda Pharmaceutical),
  • Short Interfering RNAs siRNA
  • ddRNAi short Interfering RNAs
  • ddRNAi DNA-directed RNA interference
  • HBV E antigen inhibitors include wogonin.
  • Examples of cccDNA inhibitors include BSBI-25, and CHR-101.
  • Nucleoprotein modulators may be either HBV core or capsid protein inhibitors.
  • Examples of nucleoprotein modulators include GS-4882, AB-423, AT-130, GLS4, NVR- 1221, NVR-3778, AL-3778, BAY 41-4109, morphothiadine mesilate, ARB-168786, ARB- 880, JNJ-379, RG-7907, HEC-72702, AB-506, ABI-H0731, JNJ-440 , ABI-H2158 and DVR-23.
  • WG2017013046 (Roche), WO2017016960 (Roche), WO2017017042 (Roche), WO2017017043 (Roche), WO2017061466 (Toyoma chemicals), WO2016177655 (Roche), WO2016161268 (Enanta).
  • WO2017001853 (Redex Pharma), WO2017211791 (Roche), WO2017216685 (Novartis), WO2017216686 (Novartis), WO2018019297 (Ginkgo Pharma), WO2018022282 (Newave Pharma), US20180030053 (Novartis), WO2018045911 (Zhejiang Pharma).
  • Examples of stimulators of retinoic acid-inducible gene 1 include SB-9200, SB-40, SB-44, ORI-7246, ORI-9350, ORI-7537, ORI-9020, ORI-9198, and ORI-7170, RGT-100.
  • Examples of PD-L1 inhibitors include atezolizumab, avelumab, AMP-224, MEDI- 0680, RG-7446, GX-P2, durvalumab, KY-1003, KD-033, MSB-0010718C, TSR-042, ALN-
  • Examples ofPD-1 inhibitors include the compounds disclosed in WO2017112730 (Incyte Corp), WO2017087777(Incyte Corp), WO2017017624, WO2014151634
  • BTK Tyrosine Kinase
  • BTK inhibitors include ABBV-105, acalabmtinib (ACP-196), ARQ-
  • KDM1 inhibitors include the compounds disclosed in US9186337B2 (Oryzon Genomics), GSK-2879552, and RG-6016. STING agonists
  • HBV Replication Inhibitors examples include isothiafludine, IQP-
  • Arginase inhibitors include CB-1158, C-201, and resminostat.
  • a method for treating a hyperproliferative disorder or cancer in a human or animal having or at risk of having the hyperproliferative disorder or cancer comprising administering to the human or animal a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents.
  • a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents.
  • the one or more therapeutic agents include, but are not limited to, an inhibitor, agonist, antagonist, ligand, modulator, stimulator, blocker, activator or suppressor of a gene, ligand, receptor, protein, or factor.
  • additional therapeutic agents include: Abelson murine leukemia viral oncogene homolog 1 gene (ABL, such as ABLl), Acetyl-CoA carboxylase (such as ACC 1/2), activated CDC kinase (ACK, such as ACK1), Adenosine deaminase, adenosine receptor (such as A2B, A2a, A3), Adenylate cyclase, ADP iibosyl cyclase-1, adrenocorticotropic hormone receptor (ACTH), Aerolysin, AKT1 gene, Alk-5 protein kinase, Alkaline phosphatase, Alpha 1 adrenoceptor, Alpha 2 adrenoceptor
  • Ubiquitin thioesterase-14 Ubiquitin-conjugating enzyme E2I (UBE2I, UBC9), Urease, Urokinase plasminogen activator, Uteroglobin, Vanilloid VR1, Vascular cell adhesion protein 1, vascular endothelial growth factor receptor (VEGFR), V-domain Ig suppressor of T-cell activation (VISTA), VEGF-1 receptor, VEGF-2 receptor, VEGF-3 receptor, VEGF-A, VEGF-B, Vimentin, Vitamin D3 receptor, Proto-oncogene tyrosine-protein kinase Yes, Wee- 1 protein kinase, Wilms' tumor antigen 1, Wilms' tumor protein, X-linked inhibitor of apoptosis protein, Zinc finger protein transcription factor or any combination thereof.
  • additional therapeutic agents may be categorized by their mechanism of action into, for example, the following groups:
  • ALK anaplastic lymphoma kinase inhibitors, such as alectinib, ceritinib;
  • immunosuppressives such as tacrolimus, sirolimus, azathioprine, and mycophenolate;
  • fibroblast growth factor inhibitors such as FPA14
  • DNA interference oligonucleotides such as PNT2258, AZD-9150;
  • - anti-CSFIR antibodies such as emactuzumab, LY3022855, AMG-820, FPA-008 (cabiralizumab);
  • - anti-HLA-DR antibodies such as IMMU-114;
  • anti-CEA antibodies such as RG-7813
  • CD3 antibodies such as MGD015;
  • FAP anti-fibroblast activation protein
  • IL-2R antibodies such as RG7461
  • anti-fibroblast activation protein (FAP)/TRAIL-R2 antibodies such as RG7386
  • anti-fucosyl-GMl antibodies such as BMS-986012
  • p38 MAP kinase inhibitors such as ralimetinib
  • anti- carbonic anhydrase IX antibodies such as TX-250;
  • Mucin 1 inhibitors such as GO-203-2C
  • anti-Mesothelin antibodies such as SEL-403
  • TLR-7 agonists such as TMX-101 (imiquimod);
  • NEDD8 inhibitors such as pevonedistat (MLN-4924), TAS-4464; Pleiotropic pathway modulators, such as avadomide (CC-122); - FoxMl inhibitors, such as thiostrepton;
  • RARa Retinoic acid receptor alpha
  • hypoxia inducible factor- 1 alpha inhibitors such as PT-2977, PT-2385;
  • CD122 agonists such as NKTR-214;
  • - IL-10 agonists such as AM-0010
  • EGFR/ErbB-2 inhibitors such as varlitinib
  • SMAC caspases
  • anti-PSMA antibodies such as ATL-101
  • anti-APRIL antibodies such as BION-1301;
  • Somatostatin receptor antagonist such as OPS-201
  • CEBPA gene stimulators such as MTL-501;
  • - PD-L1/VISTA antagonists such as CA-170; anti-PD-L1/TGFb antibodies, such as M7824;
  • CHK1 inhibitors such as GDC-0575, LY2606368 (prexasertib), SRA737, RG7741
  • EXH2 inhibitors such as GSK2816126
  • SESD Selective estrogen receptor downregulators
  • Faslodex® fulvestrant
  • RG6046 RG6046
  • elacestrant RAD-1901
  • AZD9496 AZD9496
  • XPOl inhibitors such as selinexor (KPT-330);
  • CCR - chemokine receptor 2 inhibitors
  • PF-04136309 CCX-872
  • BMS- 813160 CCR2/CCR5
  • thymidylate synthase inhibitors such as ONX-0801;
  • Pan-RAF inhibitors such as LY3009120, LXH254, TAK-580;
  • nucleoside analogs such as DFP- 10917
  • anti-DLL4 delta like ligand 4 antibodies, such as demcizumab;
  • Multiferon (Alfanative, Viragen), interferon alpha 1b, Roferon-A (Canferon, Ro-25-3036), interferon alfa-2a follow-on biologic (Biosidus)(Inmutag, Inter 2A), interferon alfa-2b follow-on biologic (Biosidus - Bioferon, Citopheron, Ganapar, Beijing Kawin Technology - Kaferon), Alfaferone, pegylated interferon alpha- lb, peginterferon alfa-2b follow-on biologic (Amega), recombinant human interferon alpha- lb, recombinant human interferon alpha-2a, recombinant human interferon alpha-2b, veltuzumab-IFN alpha 2b conjugate, Dynavax (SD- 101), and interferon alfa-nl (Humoferon, SM- 10500, Sumiferon);
  • Notch inhibitors such as LY3039478 (crenigacestat), tarextumab (anti-Notch2/3),
  • Focal adhesion kinase inhibitors such as VS-4718, defactinib, GSK2256098; hedgehog inhibitors, such as saridegib, sonidegib (LDE225), glasdegib and vismodegib;
  • HSP27 heat shock protein 27, HSP27
  • brivudine brivudine, apatorsen
  • - ATR inhibitors such as BAY-937, AZD6738, AZD6783, VX-803, VX-970 (berzosertib) and VX-970;
  • - mTOR/PI3K inhibitors such as gedatolisib, GSK2141795, omipalisib, RG6114;
  • CD137 agonists such as urelumab, utomilumab (PF-05082566);
  • - STING agonists such as ADU-S 100 (MIW-815), SB-11285, MK-1454, SR-8291, AdVCA0848, GSK-532, SYN-STING, MSA-1, SR-8291;
  • RXR agonists such as IRX4204
  • Oncolytic viruses such as pelareorep, CG-0070, MV-NIS therapy, HSV-1716, DS- 1647, VCN-01, ONCOS-102, TBI-1401, tasadenoturev (DNX-2401), vocimagene amiretrorepvec, RP-1, CVA21, Celyvir, LOAd-703, OBP-301;
  • DOT1L histone methyltransferase inhibitors
  • pinometostat EEZ-5676
  • - toxins such as Cholera toxin, ricin, Pseudomonas exotoxin, Bordetella pertussis adenylate cyclase toxin, diphtheria toxin, and caspase activators;
  • ROCK Rho kinase
  • ERK inhibitors such as GDC-0994, LY3214996, MK-8353;
  • IAP inhibitors such as ASTX660, debio-1143, birinapant, APG-1387, LCL-161;
  • SHP-2 inhibitors such as TN0155 (SHP-099), RMC-4550; and
  • a method of treating or preventing a hyperproliferative disorder or cancer in a human or animal having or at risk of having the hyperproliferative disorder or cancer comprises administering to the human or animal a therapeutically effective amount of a compound of the present disclosure, as disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents selected from the group consisting of apoptosis signal-regulating kinase (ASK) inhibitors; Bruton's tyrosine kinase (BTK) inhibitors; cluster of differentiation 47 (CD47) inhibitors; cyclin-dependent kinase (CDK) inhibitors; discoidin domain receptor (DDR) inhibitors; histone deacetylase (HD AC) inhibitors; indoleamine-pyrrole-2, 3-dioxygenase (IDOl) inhibitors;
  • ASK apopto
  • BTK inhibitors include, but are not limited to, (S)-6-amino-9-( 1 -(but-2-ynoyl)pyrrolidin-3 -yl)-7-(4-phenoxyphenyl)-7H- purin-8(9H)-one, acalabmtinib (ACP-196), BGB-3111, CB988, HM71224, ibmtinib, M- 2951 (evobmtinib), M7583, tirabrutinib (ONO-4059), PRN-1008, spebmtinib (CC-292), TAK-020, vecabrutinib, ARQ-531, SHR-1459, DTRMWXHS-12, TAS-5315;
  • HD AC inhibitors include, but are not limited to, abexinostat, ACY -241, AR-42, BEBT-908, belinostat, CKD-581, CS-055 (HBI-8000), CUDC-907 (fimepinostat), entinostat, givinostat, mocetinostat, panobinostat, pracinostat, quisinostat (JNJ-26481585), resminostat, ricolinostat, SHP-141, valproic acid (VAL-001), vorinostat, tinostamustine, remetinostat, entinostat;
  • JAK inhibitors inhibit JAK1, JAK2, and/or JAK3.
  • JAK inhibitors include, but are not limited to, AT9283, AZD1480, baricitinib, BMS-911543, fedratinib, filgotinib (GLPG0634), gandotinib (LY2784544), INCB039110
  • LOXL inhibitors include inhibitors of LOXL1, LOXL2, LOXL3, LOXL4, and/or LOXL5.
  • LOXL inhibitors include, but are not limited to, the antibodies described in WO 2009/017833 (Arresto Biosciences).
  • LOXL2 inhibitors include, but are not limited to, the antibodies described in WO 2009/017833 (Arresto Biosciences), WO 2009/035791 (Arresto Biosciences), and WO 2011/097513 (Gilead Biologies);
  • spongistatin nitrogen mustards such as chlorambucil, chlomaphazine, cyclophosphamide, glufosfamide, evofosfamide, bendamustine, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine,
  • nitrogen mustards such as chlorambucil, chlomaphazine, cyclophosphamide, glufosfamide, evofosfamide, bendamustine, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine,
  • chemotherapeutic agent anti-hormonal agents such as anti-estrogens and selective estrogen receptor modulators (SERMs), inhibitors of the enzyme aromatase, anti-androgens, and pharmaceutically acceptable salts, acids or derivatives of any of the above that act to regulate or inhibit hormone action on tumors.
  • SERMs selective estrogen receptor modulators
  • the immunotherapeutic agents include and are not limited to therapeutic antibodies suitable for treating subjects.
  • Some examples of therapeutic antibodies include abagovomab, ABP-980, adecatumumab, afutuzumab, alemtuzumab, altumomab, amatuximab, anatumomab, arcitumomab, bavituximab, bectumomab, bevacizumab, bivatuzumab, blinatumomab, brentuximab, cantuzumab, catumaxomab, CC49, cetuximab, citatuzumab, cixutumumab, clivatuzumab, conatumumab, dacetuzumab, dalotuzumab, daratumumab, detumomab, dinutuximab, drozitumab, duligotumab
  • the CAR comprises an antigen binding domain, a transmembrane domain, and an intracellular signalling domain.
  • the costimulatory domain comprises a functional domain of one or more proteins selected from the group consisting of CD27, CD28, 4-lBB(CD137), OX40, CD30, CD40, PD-1, ICOS, lymphocyte function-associated antigen-1 (LFA-I), CD2, CD7, LIGHT, NKG2C, B7-H3, a ligand that specifically binds with CD83, CDS, ICAM-1, GITR, BAFFR, HVEM (LIGHTR), SLAMF7, NKp80 (KLRFI), CD160, CD19, CD4, CD8alpha, CD8beta, IL2R beta, IL2R gamma, IL7R alpha, ITGA4, VLA1 , CD49a, ITGA4,
  • the transmembrane domain comprises a transmembrane domain of a protein selected from the group consisting of the alpha, beta or zeta chain of the T-cell receptor, CD28, CD3 epsilon, CD45, CD4, CDS, CDS, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137, CD154, KIRDS2, 0X40, CD2, CD27, LFA-1 (CD1 1a, CD18), ICOS (CD278), 4-lBB(CD137), GITR, CD40, BAFFR, HVEM (LIGHTR), SLAMF7, NKp8O (KLRFI), CD160, CD19, IL2Rbeta, IL2R gamma, IL7Ru, ITGA1, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CD1 1d, ITGA
  • a protein selected from the
  • GPRCSD chromosome X open reading frame 61
  • CD97 CD179a; anaplastic lymphoma kinase (ALK); Polysialic acid; placenta-specific 1 (PLACl); hexasaccharide portion of globoH glycoceramide (GloboH); mammary gland differentiation antigen (NY - BR-1); uroplakin 2 (UPK2); Hepatitis A vims cellular receptor 1 (HAVCR1); adrenoceptor beta 3 (ADRB3); pannexin 3 (PANX3); G protein-coupled receptor 20 (GPR20); lymphocyte antigen 6 complex, locus K 9 (LY6K); Olfactory receptor 51E2 (ORS IE2); TCR Gamma Alternate Reading Frame Protein (TARP); Wilms tumor protein (WT1); Cancer/testis antigen 1 (NY -ESO-1); Cancer/testis antigen 2 (LAGE-la); Melanoma

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